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Multicenter Study
. 2007 Apr 15;175(8):822-8.
doi: 10.1164/rccm.200609-1354OC. Epub 2007 Jan 18.

Association between pulmonary function and sputum biomarkers in cystic fibrosis

Nicole Mayer-Hamblett  1 , Moira L Aitken, Frank J Accurso, Richard A Kronmal, Michael W Konstan, Jane L Burns, Scott D Sagel, Bonnie W Ramsey
Affiliations
Multicenter Study

Association between pulmonary function and sputum biomarkers in cystic fibrosis

Nicole Mayer-Hamblett et al. Am J Respir Crit Care Med. .

Abstract

Rationale: Sputum biomarkers of infection and inflammation are noninvasive measures that enable quantification of the complex pathophysiology of cystic fibrosis (CF) lung disease. Validation of these biomarkers as correlates of disease severity is a key step for their application.

Objectives: We constructed a large database from four multicenter studies to quantify the strength of association between expectorated sputum biomarkers and FEV(1.)

Methods: FEV(1) (range, 25-120% predicted) and quantitative data on expectorated sputum biomarkers including free neutrophil elastase, IL-8, neutrophils, Pseudomonas aeruginosa, and Staphylococcus aureus were obtained from 269 participants (ages, 9-54 years) from 33 centers. Cross-sectional and longitudinal statistical analyses were performed to estimate associations between the markers and FEV(1), including the use of multivariable analyses.

Results: Elastase was negatively correlated with FEV(1) (correlation [r] = -0.35; 95% confidence interval [CI]: -0.46, -0.22). On average, patients with CF who differed in their elastase measurements by 0.5 log differed in their FEV(1) values by -7.3% (95% CI: -9.7, -4.6). Neutrophil counts and IL-8 were also each negatively correlated. In a multivariable regression, elastase and neutrophil counts were able to explain the majority of variation in FEV(1). Elastase was further shown to have a significant longitudinal association with FEV(1), specifically a -2.9% decline in FEV(1) (95% CI: -5.0, -0.9) per 1-log increase in elastase. Although correlated with FEV(1), bacterial densities were unable to explain clinically meaningful differences in FEV(1) within and across patients.

Conclusions: These data support the role of sputum biomarkers as correlates of disease severity in a diverse CF population.

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Figures

<b>Figure 1.</b>
Figure 1.
Scatterplots of FEV1% predicted versus each sputum marker. For IL-8, free elastase, Pseudomonas aeruginosa density, and Staphylococcus aureus density, the plots display both the average FEV1% predicted among the nondetectable values (solid diamonds) and the regression lines corresponding to the detectable values. Both the point estimate and regression line contribute to the estimate of the overall correlation of FEV1 with each marker. For neutrophil counts and percent neutrophils, the regression lines pertaining to the Pearson correlation are displayed.
<b>Figure 2.</b>
Figure 2.
Correlation estimates and 95% confidence intervals for the association between FEV1% predicted and each sputum marker. CI = confidence interval.
<b>Figure 3.</b>
Figure 3.
Estimates of the average difference in FEV1% predicted associated with an average difference in each sputum marker. Differences in FEV1% predicted are derived from the regression lines displayed in Figure 1. Because neutrophil percent is on a different scale from the other markers, only results for neutrophil counts are presented.
<b>Figure 4.</b>
Figure 4.
Longitudinal association between change in FEV1% predicted and change in free elastase. Changes in elastase that represent an increase from the limit of detection (LOD) (positive changes) and a decrease to the LOD (negative changes) are denoted by solid circles.
<b>Figure 5.</b>
Figure 5.
Power curves for a two-sample comparison of the change in free elastase.
See this image and copyright information in PMC

Comment in

References

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    1. Konstan MW, Hilliard KA, Norvell TM, Berger M. Bronchoalveolar lavage findings in cystic fibrosis patients with stable, clinically mild lung disease suggest ongoing infection and inflammation. Am J Respir Crit Care Med 1994;150:448–454. - PubMed
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    1. Sagel SD. Noninvasive biomarkers of airway inflammation in cystic fibrosis. Curr Opin Pulm Med 2003;9:516–521. - PubMed

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